The RNA exosome is an evolutionarily conserved ribonuclease complex critical for RNA processing and degradation. There are three major components of the RNA exosome ? the core, the exonuclease and the cofactors; and cofactors confer RNA substrate specificity. The majority of our current biochemical and structural understanding of the RNA exosome are from studies performed in yeast. However, mammals express many more RNA species, especially various kinds of non-coding RNAs, that either does not exist in yeast or exist at very low levels. Lost-of-function studies of RNA exosome in mammals are still scarce. We propose to study the physiological function of the mammalian cytoplasmic RNA exosome. The major cofactor of the RNA exosome in the cytoplasm is the ?superkiller (SKI)? complex, which contains RNA helicase SKIV2L and cofactor TTC37. Mutations in either SKIV2L or TTC37 gene are associated with an inherited autosomal recessive disorder, trichohepatoenteric syndrome (THES), which exhibits severe primary B-cell immunodeficiency and other clinical abnormalities. In preliminary studies, we generated Skiv2lKO and Ttc37KO mouse B cell lines as well as B-cell- specific Skiv2l conditional knockout mice. We found that Skiv2l-deficiency results in cell cycle arrest and dsDNA damage in B cells as well as early B-cell developmental arrest in mice. Therefore, we hypothesize that the SKI- RNA exosome regulates genomic stability in B cells through processing or degradation of unknown RNA targets. We will determine SKI-RNA exosome target RNA species using state-of-the-art next-gen sequencing technologies such as total RNA-seq, RIP-seq, DRIP-seq, in combination with powerful bioinformatic analysis (Aim 1). RNA surveillance by the cytoplasmic RNA exosome may be also important for other tissues and cell types. Thus, we will also investigate whether the SKI-RNA exosome is required for functions of mature B cell and other immune cells by conditional knockout (Aim 2). Together, studies proposed here will reveal the physiological function of mammalian cytoplasmic RNA exosome in B cells and support the development of strategies to treat B-cell immunodeficiency diseases such as THES.